Dopamine acts upon neurons through two families of dopamine receptors, D1-like receptors (D1Rs) and D2-like receptors (D2Rs). The D1-like receptor family consists of D1 and D5 receptors (D1), which are highly expressed in many regions of the brain. D1 mRNA has been found in the striatum and nucleus accumbens. See e.g., Missale C, Nash S R, Robinson S W, Jaber M, Caron M G “Dopamine receptors: from structure to function”, Physiological Reviews 78:189-225 (1998).
Pharmacological studies have reported that D1 and D5 receptors (D1/D5), namely D1-like receptors, are linked to stimulation of adenylyl cyclase, whereas D2, D3, and D4 receptors, namely D2-like receptors, are linked to inhibition of cAMP production See, e.g., Jose P A, et. al, “Dopamine D1 receptor regulation of phospholipase C”, Hypertension Research 18 Suppl 1:S39-42 (1995).
Dopamine D1 receptors are implicated in numerous neuropharmacological and neurobiological functions. For example, D1 receptors are involved in different types of memory function and synaptic plasticity. See e.g., Goldman-Rakic P S, Castner S A, Svensson T H, Siever L J, Williams G V “Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction”, Psychopharmacology 174(1):3-16 (2004); Castner S A, Williams G V “Tuning the engine of cognition: a focus on NMDA/D1 receptor interactions in prefrontal cortex”, Brain Cognition 63(2):94-122 (2007). In addition, D1 receptors have been implicated in a variety of psychiatric, neurological, neurodevelopmental, neurodegenerative, mood, motivational, metabolic, cardiovascular, renal, ophthalmic, endocrine, and/or other disorders described herein including schizophrenia (e.g., cognitive and negative symptoms in schizophrenia), cognitive impairment associated with D2 antagonist therapy, ADHD, impulsivity, autism spectrum disorder, Mild cognitive impairment (MCI), age-related cognitive decline, Alzheimer's dementia, Parkinson's disease, Huntington's chorea, depression, anxiety, treatment-resistant depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, post-partum depression, serotonin syndrome, substance abuse and drug dependence, Tourette's syndrome, tardive dyskinesia, drowsiness, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, dislipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, resistant edema, narcolepsy, hypertension, congestive heart failure, postoperative ocular hypotonia, sleep disorders, pain, and other disorders in a mammal. See e.g., Goulet M, Madras B K “D(1) dopamine receptor agonists are more effective in alleviating advanced than mild parkinsonism in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys”, Journal of Pharmacology and Experimental Therapy 292(2):714-24 (2000); Surmeier D J, et. al, “The role of dopamine in modulating the structure and function of striatal circuits”, Prog. Brain Research 183:149-67 (2010); Umrani D N, Goyal R K “Fenoldopam treatment improves peripheral insulin sensitivity and renal function in STZ-induced type2 diabetic rats”, Clin. Exp. Hypertension 25(4):221-233 (2003); Bina K G et al., “Dopaminergic agonists normalize elevated hypothalamic neuropeptide Y and corticotropin-releasing hormone, body weight gain, and hyperglycemia in ob/ob mice”, Neuroendocrinology 71(1):68-78 (2000).
G protein-coupled receptors (GPCRs, including D1Rs) desensitize via a common mechanism involving G protein-coupled receptor kinase (GRK) phosphorylation followed by β-arrestin binding which prevents G protein-coupling (and thus G protein activation). See Louis M. Luttrell et. al., “The role of β-arrestins in the termination and transduction of G-protein-coupled receptor signals”; J. Cell Sci., 115, 455-465 (2002). For example, D1 receptor desensitization involves agonist-induced phosphorylation of the receptor (i.e., preferential phosphorylation of the receptor that are in the agonist-occupied conformation) and β-arrestin recruitment (β-arrestin-receptor binding) that prevents G protein coupling and in turn leads to desensitization of D1 receptor's canonical G protein pathway/activation signaling [which can be measured, for example, by cyclic adenosine monophosphate (cAMP) accumulation/production]. See M. M. Lewis et. al, “Homologous Desensitization of the DIA Dopamine Receptor: Efficacy in Causing Desensitization Dissociates from Both Receptor Occupancy and Functional Potency”; JPET 286: 345-353, 1998.
In addition to their well-established role in GPCR desensitization, β-arrestins may also enable GPCR-mediated “arrestinergic” signaling by functioning as scaffolds for downstream effector molecules such as the extracellular regulated kinases (ERKs). See; Nikhil M Urs, et. al, “A Dopamine D1 Receptor-Dependent β-Arrestin Signaling Complex Potentially Regulates Morphine-Induced Psychomotor Activation but not Reward in Mice,” Neuropsychopharmacology(2011) 36, 551-558; Reiter E, et. al, “Molecular mechanism of beta-arrestin-biased agonism at seven-transmembrane receptors,” Annual review of pharmacology and toxicology. 2012; 52:179-97; and Allen J A, et al. “Discovery of beta-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy,” Proceedings of the National Academy of Sciences of the United States of America. 2011; 108(45):18488-93.
New or improved agents that modulate (such as agonize or partially agonize) D1 are needed for developing new and more effective pharmaceuticals to treat diseases or conditions associated with dysregulated activation of D1, such as those described herein.